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WO2023206444A1 - 一种曲前列尼尔软雾吸入剂 - Google Patents

一种曲前列尼尔软雾吸入剂 Download PDF

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WO2023206444A1
WO2023206444A1 PCT/CN2022/090503 CN2022090503W WO2023206444A1 WO 2023206444 A1 WO2023206444 A1 WO 2023206444A1 CN 2022090503 W CN2022090503 W CN 2022090503W WO 2023206444 A1 WO2023206444 A1 WO 2023206444A1
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sample
treprostinil
pharmaceutical preparation
preparation according
ethanol
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PCT/CN2022/090503
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English (en)
French (fr)
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戴向荣
李小羿
殷雷
陈林清
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兆科药业（广州）有限公司
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Priority to PCT/CN2022/090503 priority Critical patent/WO2023206444A1/zh
Publication of WO2023206444A1 publication Critical patent/WO2023206444A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5578—Eicosanoids, e.g. leukotrienes or prostaglandins having a pentalene ring system, e.g. carbacyclin, iloprost
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and particularly relates to an inhalable preparation of treprostinil.
  • Treprostinil chemical name [[(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-[(3S)-3-hydroxyoctane Alkyl]-1H-benzo[f]inden-5-yl]oxy]acetic acid, which has the following chemical formula:
  • treprostinil preparations of treprostinil that have been developed and marketed, namely subcutaneous or intravenous injection (remodulin, 20ml: 20mg), sustained-release tablets (Orenitram, 0.125m/0.25mg) and ultrasonic pulse atomization Inhalant (Tyvaso, 1.74mg/0.29ml).
  • remodulin subcutaneous or intravenous injection
  • Orenitram 0.125m/0.25mg
  • Tyvaso ultrasonic pulse atomization Inhalant
  • Inhalation drug delivery refers to a drug delivery method in which one or more drugs enter the lungs deep in the respiratory tract through a special drug delivery device and exert local or systemic effects.
  • Inhalation preparations mainly include three categories: inhalation aerosols, inhalation powder sprays and liquid preparations for nebulizers.
  • Tyvaso is a liquid preparation for nebulizers. It is a treprostinil inhalation system developed by United Therapeutics Corporation (see US Pat. No. 10076505), which converts the treprostinil liquid pharmaceutical preparation into a mist through the nebulizer. It takes a drug-like form and is inhaled into human lungs to achieve drug treatment effects. However, since patients with pulmonary arterial hypertension are chronic diseases, and the peak period is usually between 20 and 40 years old, moderate to mild patients who receive treatment can still go out and work normally. According to the product requirements, the aerosol inhaler Tyvaso needs to be larger and not enough to carry. Convenient specific nebulizer device.
  • treprostinil dry powder inhaler which is an inhalation powder mist. 25 micrograms of treprostinil is made into a dry granule preparation and contained in a capsule, which is inhaled into the patient's body through a dry powder inhaler.
  • the particle size of dry powder inhalants and inhalation powder aerosols is small (1-5 ⁇ m). Due to the strong interaction between particles (van der Waals force, electrostatic force and capillary force), the aggregation between particles is enhanced. , it is easy to agglomerate during the storage process, causing the particle size to change and affecting the efficacy of the drug.
  • carrier particles it is usually necessary to use carrier particles to hinder the agglomeration of the drug powder.
  • carrier particles with a particle size of 70 to 100 ⁇ m are added and mixed with drug powder with a particle size of 0.5 to 7 ⁇ m, so that the drug powder is adsorbed on the surface of the carrier particles.
  • the drug powder is separated from the carrier particles during inhalation by the patient and enters the human lungs.
  • US patent US20190030268 describes in detail a soft mist inhalation device, which is a propellant-free liquid drug inhalation device for metered administration.
  • the drug preparation solution in the atomizer is converted into an aerosol that acts on the lungs, and the drug solution is sprayed out by the atomizer using the same high-pressure method as in various countries.
  • Such inhalers are particularly suitable for use with liquid formulations of the invention.
  • This inhalation device is less than about 8cm to about 18cm long and about 2.5cm to about 5cm wide. It is compact and easy to operate. It can be taken anywhere by the patient, providing greater convenience for the patient to take medication.
  • Figure 1 shows a cross-section of the suction device under pressure.
  • the inhalation device includes nebulizer 1, liquid 2, container 3, liquid compartment 4, pressure generator 5, bracket 6, drive spring 7, delivery tube 9, check valve 10, nozzle 12, suction nozzle 13, aerosol 14, Air inlet 15, upper shell 16, internal components 17, lower shell 18.
  • Administering the inhalable solution of the present invention using the inhalation device described above can atomize a small amount of liquid, about less than about 70 ⁇ l, such as less than about 30 ⁇ l or less than about 15 ⁇ l of drug solution in one spray, so that the inhalable part of the aerosol is consistent with the treatment corresponding to the effective amount.
  • the average particle size of the sprayed aerosol is less than 10 ⁇ m or 15 ⁇ m.
  • the soft mist inhalation device disclosed in US patent US20190030268 is less than about 8cm to about 18cm long and about 2.5cm to about 5cm wide. It is compact and easy to operate. It can be taken anywhere by the patient, providing greater convenience for the patient to take medication. sex.
  • the soft mist inhalation device for treprostinil administration on the market.
  • the soft mist inhalation device is smaller and more convenient. It has lower requirements on the patient's inhalation flow rate.
  • the administration time is extended and the spray duration is long.
  • the patient only needs to breathe naturally for the drug to be fully deposited. In the lungs, it improves utilization; compared with dry powder inhalers or inhaled powder mist, it also improves the foreign body sensation in the throat and reduces the dosage.
  • the present invention provides a liquid, propellant-free pharmaceutical formulation and a method of administering the pharmaceutical formulation by aerosolizing the pharmaceutical formulation in a soft mist inhaler. and meet the required standards to enable optimal atomization of the solution in the above-mentioned inhaler. And ensure that the active substances in the pharmaceutical preparation are stable during the storage period of several years (specifically, it may be 1 or 2 years).
  • a first aspect of the present invention provides a pharmaceutical preparation, which includes: (a) treprostinil and/or a pharmaceutically acceptable salt of treprostinil; (b) a solvent; (c) a pharmaceutically acceptable salt of treprostinil. an acceptable solubilizer; and (d) a pharmaceutically acceptable preservative.
  • the pharmaceutical preparation is in liquid state.
  • the pharmaceutical preparation does not contain propellant.
  • treprostinil and pharmaceutically acceptable salts of treprostinil are one or more of their respective stereoisomers.
  • the treprostinil is a mixture of one or more of the various crystal forms of treprostinil, such as the crystal forms listed in US9822057B2, the crystal forms listed in EP2970091A1, or the ones disclosed in the following US patents Various forms of treprostinil: U.S. Patent Nos.
  • the pharmaceutically acceptable salt of treprostinil is one or more than two salts of treprostinil involved in patent US9988334B2.
  • the pharmaceutically acceptable salt of treprostinil is selected from the group consisting of treprostinil sodium salt, calcium salt, diethanolamine salt, triethanolamine salt, L-arginine salt, lysine salt, meglumine salt, ammonium salt, choline salt.
  • the content range of treprostinil or its pharmaceutically acceptable salt in the pharmaceutical preparation is about 0.086 mg/ml to about 0.6 mg/ml; in some specific embodiments, the content range is 0.080 ⁇ 0.12 mg/ml. In some embodiments, the content range is 0.13-0.18 mg/ml. In some embodiments, the content range is 0.19-0.3 mg/ml. In some embodiments, the content range is 0.13-0.18 mg/ml. The range is, 0.4 ⁇ 0.6mg/ml.
  • the solvent is selected from an organic solvent or a mixed solvent composed of water and an organic solvent; preferably, the organic solvent is selected from the group consisting of alcohols, N-methylpyrrolidone, benzyl benzoate, and dimethyl sulfide.
  • the alcohols are selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, propylene glycol, Glycerin, benzyl alcohol, phenethyl alcohol, polyethylene glycol; particularly preferably, the solvent is selected from a combination of ethanol and benzyl alcohol, or a combination of ethanol, benzyl alcohol, and water, or ethanol, benzyl alcohol and N-methylpyrrolidone or a combination of ethanol, benzyl alcohol and dimethyl sulfoxide.
  • the solvent is a mixture of water and ethanol, and ethanol has a certain penetration-promoting effect.
  • the amount of ethanol is from about 100 mg/ml to about 300 mg/ml. In some embodiments, the amount of ethanol is 100 mg/ml to 150 mg/ml. In some embodiments, the amount of ethanol is 200 mg/ml to 300 mg/ml. In some embodiments, the amount of ethanol is 160 mg. /ml to 200 mg/ml. In some embodiments, the amount of ethanol is 210 mg/ml to 250 mg/ml. In some embodiments, the amount of ethanol is 250 mg/ml to 300 mg/ml.
  • the stabilizer tromethamine in the pharmaceutical preparation is also used as an alkaline regulator or buffer.
  • the amount of tromethamine is about 0.05 mg/ml to about 0.2 mg/ml; in other embodiments, the stabilizer is sodium hydroxide, sodium citrate, or Tween-80.
  • the pharmaceutical preparation may also include one or more osmotic pressure regulators selected from the group consisting of sodium chloride, magnesium chloride, glucose, sodium chloride, phosphate, and citric acid. One or more salts.
  • sodium chloride serves as an osmotic pressure regulator, which can adjust the overall solution osmotic pressure to 300 ⁇ 30 mOsm/kg.
  • the overall chlorine The amount of sodium chloride is from about 0.1 mg/ml to about 9 mg/ml, for example, it can be 0.1 mg/ml, 0.5 mg/ml, 2.0 mg/ml, 2.5 mg/ml, 3.0 mg/ml, 3.5 mg/ml, 4.0 mg/ml, 4.5mg/ml, 5.0mg/ml, 5.5mg/ml, 6.0mg/ml, 6.5mg/ml, 7.0mg/ml, 7.5mg/ml, 8.0mg/ml, 8.5mg/ml, 9.0 mg/ml.
  • the pharmaceutical formulation may also contain one or more preservatives, which provide antimicrobial properties and may further provide stability benefits.
  • the preservatives are aromatic acids and phenolic compounds, or mixtures of these compounds.
  • the preservative is selected from, but is not limited to, Tween 80, sodium citrate, m-cresol, sodium benzoate, chlorhexidine acetate, chlorhexidine gluconate, and 50% benzalkonium chloride.
  • the preservative is 50% benzalkonium chloride, which can be used as a surfactant and a solubilizing agent at the same time.
  • the amount of 50% benzalkonium chloride is about 0.1mg/ml to about 9mg/ml, for example, it can be 0.1mg/ml, 0.5mg/ml, 2.0mg/ml, 2.5mg/ml, 3.0mg/ml, 3.5mg/ml, 4.0mg/ml, 4.5mg /ml, 5.0mg/ml, 5.5mg/ml, 6.0mg/ml, 6.5mg/ml, 7.0mg/ml, 7.5mg/ml, 8.0mg/ml, 8.5mg/ml, 9.0mg/ml.
  • the pharmaceutical preparation also contains an acidity regulator.
  • the acidity regulator is hydrochloric acid.
  • the acidity regulator can also be selected from, but is not limited to Citric acid, benzoic acid, acetic acid and other pharmaceutically acceptable acidity regulators.
  • the pH of the pharmaceutical preparation is 6.5 to 8.5.
  • the pharmaceutical formulation is an inhalable formulation.
  • the pharmaceutical preparation is an inhalable preparation, which can be atomized by a soft mist inhalation device or atomized by an air compression nebulizer.
  • the pharmaceutical preparation is administered together with a soft mist inhalation device.
  • the pharmaceutical preparation is used with the soft mist inhalation device disclosed in US Pat. No. 20190030268.
  • this pharmaceutical preparation has low requirements on the patient's inspiratory flow rate, and the patient only needs to breathe naturally for the drug to be fully deposited in the lungs. This in turn improves the delivery of inhaled drugs by increasing lung deposition.
  • the present invention provides a liquid, propellant-free pharmaceutical preparation containing treprostinil or a pharmaceutically acceptable salt thereof, so that optimal atomization of the solution can be achieved in a soft mist inhaler. And ensure that the active substances in the pharmaceutical preparation are stable during a storage period of several years (specifically, it may be 1 or 2 years).
  • Figure 1 Cross-sectional view of the soft mist inhalation device under pressure
  • Figure 2 Chemical stability of the main ingredients for 24 months.
  • the present invention intends to provide a liquid, propellant-free pharmaceutical formulation containing treprostinil and meeting the required criteria to enable optimal atomization of the solution in a soft mist inhaler.
  • the “soft mist inhaler” referred to below refers to a propellant-free liquid medicine inhalable device for metered administration previously disclosed in US patent US20190030268. This is particularly suitable for the inhalable formulations of the invention.
  • the particle size of the aerosol formed by a spray should be less than 10 microns, preferably less than 5 microns.
  • the source of treprostinil used below is Jiahegui Technology Co., Ltd., and the product batch number is L-200-727.
  • the inhalation device used by Tyvaso is Nebu-tec Optineb-irModelON-100/7, an ultrasonic grid vibration nebulizer.
  • the used models include TD-100 and TD-300.
  • Tyvaso inhalation preparation According to the marketed Tyvaso inhalation preparation, it needs to be used four times a day, with three breaths each time, and the dosage of approximately 6 micrograms per breath. Based on this effective clinical data, the solvent content of this product's treprostinil inhalation preparation was formulated.
  • the inhalable device mentioned in US patent US20190030268 can atomize a small amount of liquid in one spray, about less than 70 ⁇ l, such as less than about 30 ⁇ l or less than about 15 ⁇ l of drug solution, so this product should contain treprostinil About 0.086 mg/ml to about 0.4 mg/ml.
  • Sample 1 Prenil 8.6mg 60mg Tromethamine 10mg 10mg Sodium chloride 500mg 500mg 50% Benzalkonium Chloride 20mg 20mg 95% ethanol 20g 20g Water for Injection Add to 100ml Add to 100ml Adjust pH with HCl to 6.8 6.8
  • Sample serial number Components Concentration(mg/ml) Content determination (%) Sample 1 Prenil 0.0879 98.81 Sample 2 Prenil 0.5972 100.20
  • Sample 3 Sample 4
  • Sample 5 Prenil 30mg 30mg 30mg Tromethamine 10mg 10mg 10mg Sodium chloride 500mg 500mg 500mg 50% Benzalkonium Chloride 5mg 20mg 30mg
  • Sample serial number Components Concentration(mg/ml) Content determination (%) Sample 3 Prenil 0.2977 98.02 Sample 4 Prenil 0.3062 97.47 Sample 5 Prenil 0.2908 99.69
  • Sample 6 Prenil 30mg 30mg Sodium chloride 500mg 500mg Tromethamine 5mg 20mg 50% Benzalkonium Chloride 20mg 20mg 95% ethanol 20g 20g Water for Injection Add to 100ml Add to 100ml Adjust pH with HCl to 6.8 6.8
  • Sample serial number Components Concentration(mg/ml) Content determination (%) Sample 6 Prenil 0.3029 99.56 Sample 7 Prenil 0.3081 99.70
  • Sample 9 Prenil 30mg 30mg Sodium chloride 10mg 900mg Tromethamine 10mg 10mg 50% Benzalkonium Chloride 20mg 20mg 95% ethanol 20g 20g Water for Injection Add to 100ml Add to 100ml Adjust pH with HCl to 6.8 6.8
  • Sample serial number Components Concentration(mg/ml) Content determination (%)
  • Sample 8 Prenil 0.2977 98.24
  • Sample 9 Prenil 0.3102 97.35
  • Sample 10 Sample 11 Prenil 30mg 30mg Sodium chloride 500mg 500mg Tromethamine 10mg 10mg 50% Benzalkonium Chloride 20mg 20mg 95% ethanol 10g 30g Water for Injection Add to 100ml Add to 100ml Adjust pH with HCl to 6.8 6.8
  • Sample serial number Components Concentration(mg/ml) Content determination (%) Sample 10 Prenil 0.2977 99.02 Sample 11 Prenil 0.3102 100.15
  • Sample 12 Prenil 30mg 30mg Sodium chloride 500mg 500mg Tromethamine 10mg 10mg
  • Sample serial number Components Concentration(mg/ml) Content determination (%) Sample 12 Prenil 0.3046 97.13 Sample 13 Prenil 0.2977 99.22
  • Sample 3 sample 4 and sample 5 were atomized using a soft mist inhaler, a compressed air nebulizer (PARI SINUS) and an ultrasonic vibrating grid nebulizer (TD-7001) respectively.
  • Sprattec STP5311, Malvern was then used to measure the particle size distribution of the ejected droplets. The results are shown in Table 13.
  • the D50 of Sample 3, Sample 4 and Sample 5 are all less than 10 ⁇ m, but the particle size distribution of the soft mist inhaler changes smaller and is more uniform.
  • Example 8 Chemical stability detection of active ingredients in pharmaceutical preparations of Examples 1-7

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Abstract

本发明提供了一种含有曲前列尼尔的液态、无推进剂的药物制剂，与现有的曲前列尼尔制剂相比，其能够在软雾吸入器中实现更好的雾化效果，并且该药物制剂中的活性物质在1、2年或者更长的储存期内是稳定的。

Description

一种曲前列尼尔软雾吸入剂 技术领域
本发明属于药物制剂领域，特别涉及一种曲前列尼尔可吸入制剂。
背景技术
曲前列尼尔，化学名为[[(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-六氢-2-羟基-1-[(3S)-3-羟基辛烷基]-1H-苯并[f]茚-5-基]氧基]乙酸，其具有以下化学式：
Figure PCTCN2022090503-appb-000001
目前曲前列尼尔已开发上市的制剂有三种制剂,分别是皮下或静脉注射(瑞莫杜林，20ml：20mg)、缓释片剂(Orenitram，0.125m/0.25mg)以及通过超声波脉冲雾化的吸入剂(Tyvaso，1.74mg/0.29ml)。
根据“Thevoiceofthepatient”，FDA发布的以患者为中心的药物开发倡议报告中提到患者们寻求一种更方便、有效的治疗方式，以改善肺动脉高压带来的这一系列影响日常生活的症状。对比需要立刻停止正在进行的所有事(包括工作、上厕所、洗澡等)的给药方式，人们更希望有一种方式操作方便且能随时随地进行治疗。
吸入给药是指一种或一种以上的药物经特殊的给药装置，进入呼吸道深处的肺部，发挥局部或全身作用的给药方式。吸入制剂主要包括吸入气雾剂、吸入粉雾剂和供雾化器用的液体制剂3大类。
Tyvaso是供雾化器用的液体制剂，是联合治疗公司(UnitedTherapeuticsCorporation)开发了一种曲前列尼尔吸入系统(参见根据美国专利US10076505)，通过雾化器将由曲前列尼尔液体药物制剂转化为雾状形态，并吸入人体肺部，达到药物治疗作用。然而由于肺动脉高压病患属于慢性病，高发期一般在20～40岁，接受治疗的中轻度患者仍可正常外出活动与工作，气雾吸入剂Tyvaso根据产品要求， 需要使用体积较大、携带不够方便的特定雾化装置。雾化装置使用时，加入药液后一天清醒时需使用四次，每四小时使用一次，使用时可能需要外接电源，并在一天的使用或备用过程中设备不得平放、倾倒，因此对于外出患者日常使用气雾吸入剂Tyvaso仍不够方便，影响工作生活质量。
根据美国专利US10898494，LiquidTechnologies公司发明了一种曲前列尼尔干粉吸入剂，属于吸入粉雾剂，将25微克曲前列尼尔制成干颗粒制剂包含在胶囊中，通过干粉吸入器吸入患者体内。但是干粉吸入剂、吸入粉雾剂种药物粒子粒径较小(1～5μm)，因粒子间存在较强相互作用力(范德华力、静电力和毛细血管力)使粒子之间的聚集性增强，储存过程中极易结团而导致粒径改变并影响药效，通常需要使用载体颗粒以阻碍药粉的结团现象。一般加入粒径为70～100μm的载体颗粒，与粒径0.5～7μm的药物微粉混合，使得药物微粉吸附于载体颗粒表面，使用时，患者吸入过程中药物微粉与载体颗粒分开，进入人体肺部并沉积，如专利USPatent10076505中描述的处方为“1.06％曲前列尼尔钠、92.44％海藻糖二水合物、2％聚山梨醇酯80、4％L亮氨酸、0.27％二水柠檬酸钠和0.23％氯化钠”，使用大粒径的大分子多糖类化合物海藻糖作为载体与曲前列尼尔钠微粉混合，制成曲前列尼尔吸入剂，但在患者吸入使用过程中，仅有约20％～30％的药物输送到肺部，大量药物及辅料沉积在口腔及喉咙，最终进入胃部，并可能通过消化系统引起不良副作用。且易产生强烈异物感，对于咽部敏感患者，更容易引起应激性咳嗽，影响吸入感受。
美国专利US20190030268详细描述了一种软雾吸入装置，是一种用于计量施用的无推进剂的液体药物可吸入装置。雾化器中的药物制剂溶液被转化为作用于肺部的气雾剂，药物溶液同各国高压方式被雾化器喷出来。此类吸入器特别适用于本发明的液体制剂。此吸入装置长小于约8cm至约18cm，宽约2.5cm至约5cm，形态小巧，操作便捷，可由患者带至任何地方，为患者用药提供较大方便性。
图1显示了吸入装置承压状态下的截面。吸入装置包括喷雾器1、液体2、容器3、液体隔室4、压力发生器5、支架6、驱动弹簧7、输送管9、止回阀10、喷嘴12、吸嘴13、气雾剂14、进气口15、上壳16、内部部件17、下部壳体18。
使用上述吸入装置施用本发明的可吸入溶液，可在一次喷射中雾化少许液体，约少于70μl，例如少于约30μl或少于约15μl的药物溶液，使气雾剂可吸入部分与治疗有 效量相对应。喷射出的气雾剂的平均粒径小于10μm或15μm。此软雾吸入装置详细描述可见US20190030268。
美国专利US20190030268中公开的软雾吸入装置，此吸入装置长小于约8cm至约18cm，宽约2.5cm至约5cm，形态小巧，操作便捷，可由患者带至任何地方，为患者用药提供较大方便性。
然而市面上暂无一种针对曲前列尼尔给药的软雾吸入剂。软雾吸入装置对比市场上的Tyvaso气雾吸入装置，更小巧更方便，对患者吸气流速的要求低，同时给药时间延长，喷雾持续时间长，患者仅需自然呼吸便能药物充分地沉积在肺部，提高利用度；对比干粉吸入剂或吸入粉雾剂，又更改善喉咙异物感，并减少给药剂量。
发明内容
本发明提供了一种液态、无推进剂药物制剂以及通过将药物制剂于软雾吸入器雾化来施用药物制剂的方法。并满足所需标准，以便能够在上述吸入器中实现溶液的最佳雾化。并保证药物制剂中的活性物质在几年(具体可能为1年或2年)，储存期内是稳定的。
本发明的第一方面，提供了一种药物制剂，其包括：(a)曲前列尼尔和/或曲前列尼尔的药学上可接受的盐；(b)溶剂；(c)药学上可接受的增溶剂；和(d)药学上可接受的防腐剂。
进一步的，所述药物制剂为液态的。
进一步的，所述药物制剂不含推进剂。
进一步的，所述曲前列尼尔、曲前列尼尔的药学上可接受的盐是其各自的立体异构体中的一种或几种。
进一步的，所述曲前列尼尔为曲前列尼尔各种晶型中的一种或多种的混合物，例如US9822057B2所列举的晶型、EP2970091A1所列举的晶型、或者是如下美国专利下公开了的各种形式的曲前列尼尔：美国专利号为5153222、5234953、6521212、6756033、6803386、7199157、6054486、7417070、7384978、7879909、8563614、8252839、8536363、8410169、8232316、8609728、8350079、8349892、7999007、8658694、8653137、9029607、8765813、9050311、9,199,908、9,278,901、8,747,897、9,358,240、9,339,507、9,255,064、9,278，902、9，278,903、9,758,465；9,422,223；9,878,972；9,624,156 的美国专利；美国发布的专利申请号2009-0036465、2008-0200449、2008-0280986、2008-024697、2010-0275616、2010-0275616、2011-0184262、2011-0184295、2011-0323567、2011-0323567、2010323567、20103-0323567、2016-0030356、2016-0030356、2016-0051505、2016-0051505、2016-0030355、2016-0143868、2010-0328232、2015-0148414、2016-0045470、2016-0129087、2010-0129087、2010-0095432、2018-0153847的专利和PCT出版物号为WO00/57701、WO2016010538、WO2016038532、WO2016038532、WO2018/058124的专利。
在一些具体实施方案中，所述曲前列尼尔的药学上可接受的盐为专利US9988334B2所涉及的曲前列尼尔的盐的一种或两种以上。
在一些具体实施方式中，所述曲前列尼尔的药学上可接受的盐选自曲前列尼尔钠盐、钙盐、二乙醇胺盐、三乙醇胺盐、L-精氨酸盐、赖氨酸盐、葡甲胺盐、铵盐、胆碱盐中的一种。
进一步的，所述的药物制剂中曲前列尼尔或其药学上可接受的盐的含量范围是约0.086mg/ml至约0.6mg/ml；在一些具体实施方式中，该含量范围是0.080～0.12mg/ml,在一些具体实施方式中，该含量范围是0.13～0.18mg/ml,在一些具体实施方式中，该含量范围是0.19～0.3mg/ml，在一些具体实施方式中，该含量范围是,0.4～0.6mg/ml。
进一步的，所述溶剂所述溶剂选自有机溶剂或者为水和有机溶剂组成的混合溶剂；优选的，所述有机溶剂选自醇类、N-甲基吡咯烷酮、苯甲酸苄酯、二甲亚砜中的一种或多种组合；更优选的，所述醇类选自甲醇、乙醇、正丙醇，异丙醇，正丁醇，异丁醇、叔丁醇、乙二醇、丙二醇、甘油、苯甲醇、苯乙醇、聚乙二醇；特别优选的，所述溶剂选自乙醇、苯甲醇的组合，或乙醇、苯甲醇、水的组合，或乙醇、苯甲醇和N-甲基吡咯烷酮的组合，或乙醇、苯甲醇和二甲基亚砜的组合。
在一些具体实施方式中，所述溶剂是水和乙醇的混合物，同时乙醇具有一定促渗作用。在一个具体实施方式中，乙醇的量在约100mg/ml至约300mg/ml。在一些具体实施方式中，乙醇的量为100mg/ml至150mg/ml,在一些具体实施方式中，乙醇的量为200mg/ml至300mg/ml，在一些具体实施方式中，乙醇的量为160mg/ml至200mg/ml，在一些具体实施方式中，乙醇的量为210mg/ml至250mg/ml，在一些具体实施方式中，乙醇的量为250mg/ml至300mg/ml。
进一步的，在一些具体实施方式中，所述的药物制剂中的稳定剂氨丁三醇，同时氨丁三醇作为碱性调节剂或缓冲剂使用，优选的，氨丁三醇的量在约0.05mg/ml至约0.2mg/ml；在另一些具体实施方式中，稳定剂是氢氧化钠、柠檬酸钠、或吐温-80。
在一些实施方式中，所述的药物制剂还可以包含一种或多种渗透压调节剂，所述渗透压调节剂选自氯化钠、氯化镁、葡萄糖、氯化钠、磷酸盐、枸橼酸盐的一种或多种，在一些具体实施方式中，氯化钠作为渗透压调节剂，可以将整体溶液渗透压调节至300±30mOsm/kg为最佳，在一个具体实施方式中，整体氯化钠的量在约0.1mg/ml至约9mg/ml，例如可以是0.1mg/ml、0.5mg/ml、2.0mg/ml、2.5mg/ml、3.0mg/ml、3.5mg/ml、4.0mg/ml、4.5mg/ml、5.0mg/ml、5.5mg/ml、6.0mg/ml、6.5mg/ml、7.0mg/ml、7.5mg/ml、8.0mg/ml、8.5mg/ml、9.0mg/ml。
进一步的，所述的药物制剂还可以包含一种或多种防腐剂,其提供抗微生物特性并且可以进一步提供稳定性益处。优选的，防腐剂是芳酸和酚类化合物,或这些化合物的混合物。在一些具体实施方式中，防腐剂选自但不限于吐温80、柠檬酸钠、间甲酚、苯甲酸钠、醋酸氯己定、葡糖糖酸氯己定、50％苯扎氯铵的一种或多种的组合；在一些具体实施方案中，所述防腐剂为50％苯扎氯铵，其同时可作为表面活性剂及增溶剂，优选的，50％苯扎氯铵的量在约0.1mg/ml至约9mg/ml，例如可以是0.1mg/ml、0.5mg/ml、2.0mg/ml、2.5mg/ml、3.0mg/ml、3.5mg/ml、4.0mg/ml、4.5mg/ml、5.0mg/ml、5.5mg/ml、6.0mg/ml、6.5mg/ml、7.0mg/ml、7.5mg/ml、8.0mg/ml、8.5mg/ml、9.0mg/ml。
在一些实施方式中，所述的药物制剂还包含酸度调节剂，在一个具体实施方式中，所述酸度调节剂为盐酸，在另外一些具体实施方式中，酸度调节剂还可以选自但不限于柠檬酸、苯甲酸、乙酸等其他药学上可接受的酸度调节剂。优选的，所述药物制剂的pH为6.5～8.5。
在一些具体实施方式中，所述药物制剂为可吸入制剂。
在另一些具体实施方式中，所述的药物制剂为可吸入制剂，其可由软雾吸入装置雾化或空气压缩雾化器雾化施用，优选的，结合软雾吸入装置一起施用所述药物制剂，进一步优选的，以美国专利US20190030268中公开的软雾吸入装置使用所述的药物制剂。
进一步的，本药物制剂对患者吸气流速的要求低，患者仅需自然呼吸便能药物充分地沉积在肺部。再通过增加肺部沉积来改善吸入药物的递送。
本发明提供的一种含有曲前列尼尔或其药物上可接受的盐的液态、无推进剂的药物制剂，以便能够在软雾吸入器中实现溶液的最佳雾化。并保证药物制剂中的活性物质在几年(具体可能为1年或2年)的储存期内是稳定的。
附图说明
图1软雾吸入装置承压状态截面图；
图2主要成分24月的化学稳定性。
具体实施方式
本发明拟提供一种含有曲前列尼尔的液态、无推进剂的药物制剂，并满足所需标准，以便能够在软雾吸入器中实现溶液的最佳雾化。
以下所称的“软雾吸入器”是指此前美国专利US20190030268公开的一种用于计量施用的无推进剂的液体药物可吸入装置。其特别适用于本发明的可吸入制剂。由一个喷射形成的气雾粒径应小于10微米，更优为小于5微米。
以下所使用的曲前列尼尔的来源为佳和桂科技股份有限公司，产品批号为L-200-727。
Tyvaso使用的吸入装置为Nebu-tec Optineb-irModelON-100/7，一种超声波网格震动雾化器，使用过的型号有TD-100和TD-300。
根据已上市Tyvaso吸入制剂，每日需使用四次，每次3次呼吸，每次呼吸约6微克的药量，根据此有效临床数据，制定本品曲前列尼尔可吸入制剂的溶剂含量。
美国专利US20190030268中提到的可吸入装置，可在一次喷射中雾化少许液体，约少于70μl，例如少于约30μl或少于约15μl的药物溶液，故本品对应应含曲前列尼尔约0.086mg/ml至约0.4mg/ml。
实施例1样品1和样品2可吸入溶液的制备
成分列在表1中，按表1将曲前列尼尔和50％苯扎氯铵置于100ml量瓶中。加入95％乙醇溶解。加入氨丁三醇和氯化钠，加入适量注射用水，超声使完全溶解。最后用纯化水定容，并调节至相应pH。
表3样品1和样品2的100ml可吸入溶液的成分含量
组分 样品1 样品2
曲前列尼尔 8.6mg 60mg
氨丁三醇 10mg 10mg
氯化钠 500mg 500mg
50％苯扎氯铵 20mg 20mg
95％乙醇 20g 20g
注射用水 加至100ml 加至100ml
用HCl调节pH至 6.8 6.8
表2样品1和样品2的可吸入溶液的含量测定
样品编号 组分 浓度(mg/ml) 含量测定(％)
样品1 曲前列尼尔 0.0879 98.81
样品2 曲前列尼尔 0.5972 100.20
实施例2样品3、样品4和样品5的可吸入溶液的制备
成分列在表3中，按表3将曲前列尼尔和50％苯扎氯铵置于100ml量瓶中。加入95％乙醇溶解。加入氨丁三醇和氯化钠，加入适量注射用水，超声使完全溶解。最后用纯化水定容，并调节至相应pH。
表3样品3、样品4和样品5的100ml可吸入溶液的成分含量
组分 样品3 样品4 样品5
曲前列尼尔 30mg 30mg 30mg
氨丁三醇 10mg 10mg 10mg
氯化钠 500mg 500mg 500mg
50％苯扎氯铵 5mg 20mg 30mg
95％乙醇 20g 20g 20g
注射用水 加至100ml 加至100ml 加至100ml
用HCl调节pH至 6.8 6.8 6.8
表4样品3、样品4和样品5的可吸入溶液的含量测定
样品编号 组分 浓度(mg/ml) 含量测定(％)
样品3 曲前列尼尔 0.2977 98.02
样品4 曲前列尼尔 0.3062 97.47
样品5 曲前列尼尔 0.2908 99.69
实施例3样品6和样品7的可吸入溶液的制备
成分列在表5中，按表5将曲前列尼尔和50％苯扎氯铵置于100ml量瓶中。加入95％乙醇溶解。加入氨丁三醇和氯化钠，加入适量注射用水，超声使完全溶解。最后用纯化水定容，并调节至相应pH。
表5样品6和样品7的100ml可吸入溶液的成分含量
组分 样品6 样品7
曲前列尼尔 30mg 30mg
氯化钠 500mg 500mg
氨丁三醇 5mg 20mg
50％苯扎氯铵 20mg 20mg
95％乙醇 20g 20g
注射用水 加至100ml 加至100ml
用HCl调节pH至 6.8 6.8
表6样品6和样品7的可吸入溶液的含量测定
样品编号 组分 浓度(mg/ml) 含量测定(％)
样品6 曲前列尼尔 0.3029 99.56
样品7 曲前列尼尔 0.3081 99.70
实施例4样品8和样品9的可吸入溶液的制备
成分列在表7中，按表7将曲前列尼尔和50％苯扎氯铵置于100ml量瓶中。加入95％乙醇溶解。加入氨丁三醇和氯化钠，加入适量注射用水，超声使完全溶解。最后用纯化水定容，并调节至相应pH。
表7样品8和样品9的100ml可吸入溶液的成分含量
组分 样品8 样品9
曲前列尼尔 30mg 30mg
氯化钠 10mg 900mg
氨丁三醇 10mg 10mg
50％苯扎氯铵 20mg 20mg
95％乙醇 20g 20g
注射用水 加至100ml 加至100ml
用HCl调节pH至 6.8 6.8
表8样品8和样品9的可吸入溶液的含量测定
样品编号 组分 浓度(mg/ml) 含量测定(％)
样品8 曲前列尼尔 0.2977 98.24
样品9 曲前列尼尔 0.3102 97.35
实施例5样品10和样品11的可吸入溶液的制备
成分列在表9中，按表9将曲前列尼尔和50％苯扎氯铵置于100ml量瓶中。加入95％乙醇溶解。加入氨丁三醇和氯化钠，加入适量注射用水，超声使完全溶解。最后用纯化 水定容，并调节至相应pH。
表9样品10和样品11的100ml可吸入溶液的成分含量
组分 样品10 样品11
曲前列尼尔 30mg 30mg
氯化钠 500mg 500mg
氨丁三醇 10mg 10mg
50％苯扎氯铵 20mg 20mg
95％乙醇 10g 30g
注射用水 加至100ml 加至100ml
用HCl调节pH至 6.8 6.8
表10样品10和样品11的可吸入溶液的含量测定
样品编号 组分 浓度(mg/ml) 含量测定(％)
样品10 曲前列尼尔 0.2977 99.02
样品11 曲前列尼尔 0.3102 100.15
实施例6样品12和样品13的可吸入溶液的制备
成分列在表11中，按表9将曲前列尼尔和50％苯扎氯铵置于100ml量瓶中。加入95％乙醇溶解。加入氨丁三醇和氯化钠，加入适量注射用水，超声使完全溶解。最后用纯化水定容，并调节至相应pH。
表11样品12和样品13的100ml可吸入溶液的成分含量
组分 样品12 样品13
曲前列尼尔 30mg 30mg
氯化钠 500mg 500mg
氨丁三醇 10mg 10mg
50％苯扎氯铵 15mg 15mg
95％乙醇 20g 20g
注射用水 加至100ml 加至100ml
用HCl调节pH至 6.5 8.5
表12样品12和样品13的可吸入溶液的含量测定
样品编号 组分 浓度(mg/ml) 含量测定(％)
样品12 曲前列尼尔 0.3046 97.13
样品13 曲前列尼尔 0.2977 99.22
实施例7
将样品3、样品4和样品5分别使用软雾吸入器、压缩空气雾化器(PARI SINUS)和超声震动网格雾化器(TD-7001)雾化。再用Sprattec(STP5311,Malvern)测量喷射出来的液滴的粒径分布。结果见表13，样品3、样品4和样品5的D50均小于10μm，但软雾吸入器的粒径分布变化更小，也更均匀。
表13样品3、样品4和样品5雾化粒径测定
Figure PCTCN2022090503-appb-000002
Figure PCTCN2022090503-appb-000003
实施例8实施例1-7的药物制剂中活性成分的化学稳定性检测
实施例1-7中的样品1、样品2、样品3、样品5、样品7、样品9、样品11、样品12和样品13在15℃-25℃条件下放置6月、12月和24月时分别测定其含量，结果见表14，趋势对比见图2。
表14实施例1-7稳定性考察结果
Figure PCTCN2022090503-appb-000004
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种液态、无推进剂的药物制剂，其包括：(a)曲前列尼尔或曲前列尼尔的药学上可接受的盐；(b)溶剂；(c)药学上可接受的增溶剂；和(d)药学上可接受的防腐剂。
  2. 如权利要求1所述的药物制剂，其特征在于，曲前列尼尔或曲前列尼尔的药学上可接受的盐的含量范围为0.086～0.6mg/ml。
  3. 如权利要求1所述的药物制剂，其特征在于，所述溶剂是水和乙醇的混合物，乙醇的含量为100～300mg/ml。
  4. 如权利要求1所述的药物制剂，其特征在于，所述增溶剂为氨丁三醇，氨丁三醇的含量为0.05～0.2mg/ml。
  5. 如权利要求1所述的药物制剂，其特征在于，其还包含渗透压调节剂，其渗透压为300±30mOsm/kg。
  6. 如权利要求5所述的药物制剂，其特征在于，所述渗透压调节剂选自葡萄糖、氯化钠、氯化镁、磷酸盐或枸橼酸盐中的一种或多种。
  7. 如权利要求1所述的药物制剂，其特征在于，所述防腐剂为吐温80、柠檬酸钠、间甲酚、苯甲酸钠、醋酸氯己定、葡糖糖酸氯己定、50％苯扎氯铵的一种或多种的组合。
  8. 如权利要求1所述的药物制剂，其特征在于，其还包含酸度调节剂，其pH为6.5～8.5。
  9. 如权利要求8所述的药物制剂，其特征在于，所述酸度调节剂选自盐酸、柠檬酸、苯甲酸、乙酸中的一种或多种。
  10. 如权利要求1-9任一所述的药物制剂，其特征在于，其为可吸入制剂，可由软雾吸入装置雾化或空气压缩雾化器雾化施用。
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